Amphibians in general, and poison frogs in particular, have been a significant source of biologically active natural products.1,2 A number of frog-skin alkaloids have been shown to have activity at nicotinic acetylcholine receptors.3,4 The ability of poison frogs to sequester alkaloids from their diet results in a unique complexity and to date over 800 alkaloids in more than 20 structural classes have been characterized.
In 1992, epibatidine (1) was isolated and characterized from the frog Epipedobates anthonyi (formerly Epipedobates tricolor, Boulenger, 1899). This compound has become one of the most well-studied members of the frog alkaloids due to its potent analgesic activity resulting from activation of nicotinic receptors. However, the chemical complexity of this extract (over 80 alkaloids) has prompted the investigation of other alkaloids, including epiquinamide (2). Although the activity initially ascribed to this compound was later found to be due to a cross-contamination artifact, other compounds within this extract were also found to have nicotinic activity, such as the known N-methylepibatidine.
Nicotinic agonists, which enhance action at nicotinic acetylcholine receptors, have been shown to possess useful clinical activity in a number of diseases and disorders, such as in the treatment of dementia caused by Alzheimer's disease, treatment of tobacco dependence, treatment of glaucoma, and for use as short acting muscle relaxants. While certain nicotinic acetylcholine receptor agonists have been proposed, there remains an unmet need in the art for additional nicotinic acetylcholine receptor agonists.